Breast cancer is the second leading cause of cancer death among women in the US. At the time of diagnosis, less than 10% of women are presented with a metastatic disease. However, when relapse occurs after definitive therapy, the majority of patients end up with disseminated metastases rather than an isolated local recurrence. Taxanes (paclitaxel and docetaxel) have remarkable anticancer efficacy for the treatment of breast, ovarian, prostate and lung cancers. However, they have poor selectivity and high toxicity which are the most important factors for discontinuation of cancer chemotherapy. Trastuzumab in combination with chemotherapy is often used as first line therapy for metastatic HER-2 positive breast cancers. Patients develop acquired resistance within months to years; while other patients demonstrate intrinsic resistance (de novo resistance). Inhibition of HSP90 has the potential to shut down multiple oncogenic signaling pathways simultaneously. With the recent discovery of feedback loops that counteract the efficacy of molecularly targeted agents, one solution to combat feedback loops is to attack cancers with a multimodal inhibitor that simultaneously inhibits multiple signaling nodes using HSP90 inhibitors which can also combat the emergence of resistance mutations. The therapeutic potential of HSP90 inhibition is being evaluated extensively in a number of clinical trials, including 17-AAG (now in phase III clinical trials). Simultaneous combination therapy is critical in circumventing drug resistance for the treatment of HER-2-positive breast cancers. However, the ability to safely and specifically deliver multiple drugs with non-overlapping mechanisms of action has been challenging. To overcome these issues, we plan to develop multifunctional polymeric nanoparticles to test the hypothesis that tri-modal combination nanoparticles will prove more effective with less toxicity than current standard of care therapies for HER-2 positive breast cancers. These multi-functional polymeric nanoparticles will incorporate paclitaxel (Taxol) and 17-AAG within the core, but will also be decorated on the surface with trastuzumab as a targeting moiety to specifically target HER-2 receptors as well as function as a molecular targeted therapeutic agent. We hypothesize that these targeted nanoparticles will be active in vitro against HER-2 positive breast cancer cell lines as well as HER-2 positive trastuzumab and/or lapatinib resistant breast cancer cell lines, and that they will show in vivo efficacy in mouse xenograft models of HER-2 positive drug resistant tumors. Aim 1: We will synthesize stealth hydrolysable crosslinked trastuzumab surface-targged- P (LLA-HEMA) nanoparticles. Aim 2: We will fabricate and characterize drug (paclitaxel and 17-AAG)- loaded and rhodamine-123-loaded stealth hydrolysable crosslinked trastuzumab surface-tagged- P(LLA-HEMA) nanoparticles and carry out internalization and cytotoxicity studies. Aim 3: We will carry out biodistribution studies on Bodipy(R)-labeled stealth hydrolysable crosslinked trastuzumab surface-tagged- P(LLA-HEMA) nanoparticles and efficacy studies on drug (paclitaxel and 17-AAG)- loaded stealth hydrolysable crosslinked trastuzumab surface-tagged- P(LLA-HEMA) nanoparticles and internalization and cytotoxicity studies. This work will, when successfully completed, bring to bear the combined power of a chemotherapeutic agent, molecular targeted therapy and HSP90 inhibitor, to overcome HER-2 resistance with minimal toxicity.